Nivolumab-Based Regimens Extend Survival in Advanced Gastroesophageal Cancer Based on Molecular Biomarkers

Nivolumab-based immunotherapy shows promise in extending survival for patients with advanced gastroesophageal adenocarcinoma, particularly in those with specific molecular and genomic profiles, according to study results published in Nature Medicine.

“We describe in-depth biomarker analyses from baseline tumors from the CheckMate 649 study to examine the association of biomarkers with survival outcomes in patients treated with nivolumab-plus-chemotherapy or nivolumab-plus-ipilimumab versus chemotherapy,” authors explained.

The CheckMate 649 study revealed that nivolumab plus chemotherapy, as well as nivolumab combined with ipilimumab, can improve overall survival compared to chemotherapy alone, depending on tumor subtype and genetic characteristics.

The aim of the CheckMate 649 biomarker analysis was to explore how baseline tumor biomarkers, including genomic subtypes, tumor mutational burden (TMB), microsatellite instability (MSI), and gene expression signatures (GES), correlate with overall survival in patients treated with nivolumab-based regimens.

In this large-scale analysis, of the 1581 patients in the nivolumab-plus-chemotherapy cohort, 685 (43%) had tumors evaluable by whole-exome sequencing (WES), and 809 (51%) by RNA sequencing. Similarly, in the nivolumab-plus-ipilimumab group (n = 813), 366 (45%) and 402 (49%) were evaluable by WES and RNA sequencing, respectively. Overall, patients with hypermutated or microsatellite instability–high (MSI-high) tumors showed the most substantial survival benefits when treated with either nivolumab-plus-chemotherapy (HR, 0.37; 95% CI, 0.15–0.90) or nivolumab-plus-ipilimumab (HR, 0.27; 95% CI, 0.07–1.06). In contrast, patients with chromosomal instability (CIN) tumors derived less benefit from nivolumab-based treatments. For those with high tumor mutational burden (TMB), survival was also notably extended with nivolumab-plus-chemotherapy (HR, 0.48; 95% CI, 0.25–0.91) and nivolumab-plus-ipilimumab (HR, 0.31; 95% CI, 0.10–0.95).

Beyond these genomic features, low angiogenesis GES scores and high regulatory T-cell (Treg) GES scores were associated with improved survival for patients receiving nivolumab-plus-chemotherapy and nivolumab-plus-ipilimumab, respectively. Safety data revealed no new signals, with COVID-19 and upper respiratory infections as the most common adverse events.

“This exploratory biomarker analysis from the CheckMate 649 study identified patient populations with gastric, gastroesophageal junction and esophageal adenocarcinoma that seem to derive greater OS benefit from first-line nivolumab-plus-chemotherapy or potential benefit from nivolumab-plus-ipilimumab versus chemotherapy,” concluded the study authors.

Reference

Shitara K, Janjigian YY, Ajani J, et al. Nivolumab plus chemotherapy or ipilimumab in gastroesophageal cancer: exploratory biomarker analyses of a randomized phase 3 trial. Nat Med. 2025;31(5):1519-1530. doi:10.1038/s41591-025-03575-0